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Background: Patients with atopic dermatitis (AD) often show the infiltration of basophils in the affected skin. Because basophils represent only a minor fraction among cellular infiltrates in the skin lesion, the functional significance of skin-infiltrating basophils in AD pathogenesis remains ill-defined. In this study, we aimed to clarify the role of basophils and their effector molecules triggering skin inflammation in oxazolone (OX)-induced murine model of AD. Methods: A panel of mouse strains were sensitized and repeatedly challenged with topical applications of OX to induce AD-like skin inflammation. Both local and systemic Th2 immune responses were analyzed. Results: Basophils progressively accumulated in the skin lesion but barely in draining lymph nodes (LNs). When basophils were depleted during the elicitation phase, skin inflammation was ameliorated while Th2 cell differentiation in draining LNs remained intact. The expression of IL-4 was highly upregulated in the affected skin, and basophils turned out to be the major producers of IL-4 among cellular infiltrates, suggesting the involvement of basophil-derived IL-4 in the Th2 skin inflammation. Indeed, basophil-specific IL-4-deficient mice displayed attenuated skin inflammation with a marked reduction of IL-4 in the skin lesion, even though cutaneous basophil infiltration and serum levels of IgE remained intact. Conclusions: Skin-infiltrating basophils promoted OX-induced AD-like skin inflammation through their local production of IL-4, rather than the induction of Th2 cell differentiation in draining LNs. This study suggests that the selective targeting of basophils could be a beneficial strategy in the treatment of a certain type of AD.

Promyelocytic leukemia nuclear bodies (PML-NBs) comprise multiple regulatory factors and play crucial roles in the maintenance of cellular integrity, while unregulated activation of PML-NBs induces death and premature senescence. Hence, the function of PML-NBs must be directed properly; however, the mechanism that regulates PML-NBs remains unclear. In this paper, we show that PML-NBs are disintegrated by an AT-rich interaction domain family protein E2FBP1/hDril1 through specific desumoylation of promyelocytic leukemia protein (PML) in vivo and in vitro. RNA interference-mediated downregulation of E2FBP1/hDril1 results in hyperplasis of PML-NBs and consequent commitment to PML-dependent premature senescence. Thus, the function of E2FBP1/hDril1 is required for maintenance of survival potential of the cells. Our data suggest a novel mechanism to govern cellular integrity through the modulation of nuclear depots.

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